Effects of a Diet Rich in Advanced Glycation End Products in the Rat Remnant Kidney Model Katarı ´na S ˇ ebekova ´ , MD, PhD, Veronika Faist, NatDr, PhD, Thomas Hofmann, NatDr, PhD, Reinhard Schinzel, NatDr, PhD, and August Heidland, MD ● Background: Food-derived advanced glycation end product (AGE)-analogues, the Maillard reaction products (MRPs), are formed during heat processing. Mainly low molecular weight MRPs are absorbed partially into the circulation and subsequently excreted in urine. In the presence of renal insufficiency, their removal is impaired, with a prolonged increase in plasma levels. Although bioactivity of orally absorbed MRPs has been shown in both experimental and human studies, its relevance in renal insufficiency still is unclear. Methods: In the rat remnant- kidney model (five-sixth nephrectomy [5/6NX]), effects of an AGE-rich and an AGE-poor diet were investigated during a period of 6 weeks and compared with effects in sham-operated healthy (control [CTRL]) rats on renal function (serum creatinine level and proteinuria). In the AGE-rich diet, 25% wt/wt of cornstarch was replaced by bread crusts. Results: Despite pair feeding, the AGE-rich diet resulted in a significant increase in body weight, including weight of the kidney, liver, and heart, in both the CTRL and experimental groups. The AGE-rich diet also enhanced proteinuria in CTRL rats by a factor of 2 and in 5/6NX rats by a factor of 8. Renal function (serum creatinine level and creatinine clearance) in healthy CTRLs did not change significantly. In the 5/6NX group, glomerular filtration rate (GFR) tended to even higher levels. Conclusion: Administration of an AGE-rich diet for 6 weeks does not impair GFR, but induces an increase in proteinuria, in particular, in the 5/6NX rats, indicating detrimental effects on the kidney. Am J Kidney Dis 41(S1):S48-S51. © 2003 by the National Kidney Foundation, Inc. INDEX WORDS: Advanced glycation end products (AGEs); nutrition; renal disease; proteinuria. A DVANCED GLYCATION end products (AGEs) accumulate during aging, in diabe- tes mellitus and acute and chronic renal failure, as well as in liver cirrhosis. 1-5 Mainly, their accumulation in the kidney and cardiovascular system is assumed to exert toxic effects. To date, the toxicity of parenterally administered AGE- modified proteins has been shown by various animal models, whereas coadministration of sub- stances antagonizing or preventing AGE actions substantially ameliorated the renal and vascular pathological states. 6-11 Food-derived AGE-analogues, the Maillard re- action products (MRPs), are formed during their technological heat processing, household heat- ing, and long-term storage. For endogenously formed AGEs, the chemical structure of MRPs is yet poorly defined. In foods, MRPs determine the sensory properties contributing to the forma- tion of texture, aroma, and color of the processed food, giving it its appeal. Moreover, certain MRPs have been shown to exert antioxidant, oxygen, and/or radical scavenging capacity in vitro (re- viewed in 12,13 ). However, (1) their fate in the organism, (2) potential bioactivity, and (3) contri- bution to and/or modulating action on the toxic- ity of endogenously formed AGEs, in particular, in renal insufficiency, largely remain unclear. Studies of rats and healthy humans concur- rently have shown that after a single oral dose, approximately 10% to 30% of ingested MRPs are absorbed into the circulation, which applies espe- cially to low molecular weight MRPs (reviewed in 14 ). Recent positron emission tomography stud- ies of rats with fluorine 18 ([ 18 F]-benzoyl)- carboxymethyllysine (CML) and [ 18 F- benzoyl]- carboxyethyllysine administered as a single bolus dose showed a first-pass effect in the liver, fol- lowed by rapid and almost complete elimination through the kidney within the first 2 hours (84% and 93%, respectively). 15 After oral administra- tion of CML-modified casein to rats, the greatest From the Institute of Preventive and Clinical Medicine, Bratislava, Slovak Republic; Institute for Human Nutrition and Food Science, University Kiel; German Research Insti- tute for Food Chemistry, Garching; Institute of Physiologi- cal Chemistry II, Biocenter; and Department of Internal Medicine, University Wuerzburg, Germany. We acknowledge the Commemorative Association for the Japan World Exposition (1970), Japanese Association of Dialysis Physicians, Osaka Pharmaceutical Manufacturers Association, and the Pharmaceutical Manufacturers Associa- tion of Tokyo for financial support to publish this supple- ment. Address reprint requests to August Heidland, MD, Depart- ment of Internal Medicine, University of Wuerzburg, Jozef- Schneider 2, 970 80 Wuerzburg, Germany. E-mail: august. heidland@ t-online.de © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4103-0111$30.00/0 doi:10.1053/ajkd.2003.50084 American Journal of Kidney Diseases, Vol 41, No 3, Suppl 1 (March), 2003: pp S48-S51 S48